Minimal Nucleation State of α-Synuclein Is Stabilized by Dynamic Threonine-Water Networks

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• The first structures of alpha-synuclein (αSyn) fibrils have been determined.
• Understanding the nucleation and stabilization of αSyn fibrils is crucial for neurodegenerative diseases.

Purpose of the Study:

• To determine the minimal nucleation size of the 11-amino acid NAC protofibril.
• To investigate the dynamic behavior of crystal waters within the αSyn steric zipper.

Main Methods:

• Molecular dynamics simulations.
• Analysis of X-ray crystallography and NMR structures of αSyn.

Main Results:

• Protofibrils with more than eight chains are thermodynamically stabilized.
• Stabilization is achieved through protection of the fibril core and ordering of end strands.
• Crystal water molecules are stably coordinated by threonine residues (Thr72, Thr75) in the β-sheet.

Conclusions:

• The identified Thr-water networks may play a role in enhanced fibril nucleation observed in the familial A53T mutation.
• These findings provide insights into the structural dynamics and stabilization mechanisms of αSyn fibrils.